This project is focused on the cellular pathology of the schizophrenic brain. The fundamental hypothesis to be explored is that disturbances of neuronal migration and/or preprogrammed cell death in the second trimester of pregnancy will compromise the associative circuitry interconnecting prefrontal and medial temporal cortex and mediodorsal (MD) thalamus. We have observed that interstitial neurons of white matter beneath the prefrontal and temporal cortex are maldistributed in schizophrenia which is compatible with the suggestion that their normal migration to the cortex or their developmentally-regulated death cycle could have been disrupted in the second trimester of pregnancy. A disturbance in cell settling patterns in the cortex could cause a disruption of intrinsic cortical connectivity which is compatible with hypofrontality in schizophrenia and could result in secondary effects in MD and in medial temporal cortex. Neuronal pathology has been reported in both of these brain regions in schizophrenia. This pathology could result in a functional disconnection in the proposed "psychosis" circuitry, a concomitant of which is down regulation of gene expression for transmitter and receptor related molecules. A unique collection of schizophrenic and control brains has been evaluated clinically, collected, matched for age, sex and autolysis time and prepared for analysis by a novel method developed in the last grant period. Anatomical, histochemical, immunohistochemical and in situ hybridization methods will be applied to the targeted brain areas to detect changes in specific cell populations, in components of the inhibitory and excitatory cortical and thalamic circuitry, and in features indicative of disordered neuronal migration or programmed cell death. Specific research aims include: quantify specific neuronal populations in the medial temporal and prefrontal cortex and MD, evaluate the relative densities of immunocytochemically defined afferent fiber systems in the cortex and MD, quantify potential changes in gene expression for transmitter and receptor related molecules, quantify and assess morphology; continue to make prospective clinical evaluations and collect brains of schizophrenic and control subjects.